2. Academic Validation
  3. Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer's disease

Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer's disease

  • Mol Neurodegener. 2025 Jul 23;20(1):84. doi: 10.1186/s13024-025-00875-4.
Pingao Zhang # 1,  Chenghuan Song # 1,  Jiyun Shi 1,  Zijie Wei 1,  Jing Wang 1 2,  Wanying Huang 1,  Rui Zhang 1,  Jintao Wang 1 3,  Xiaoli Yang 4,  Gang Wang 3 5,  Xiaoling Gao 1,  Yongfang Zhang 6,  Hongzhuan Chen 7 8,  Hao Wang 9
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 2 Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 3 Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 4 Department of Neurology, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China.
  • 5 Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 6 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. 182430@shsmu.edu.cn.
  • 7 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. yaoli@shsmu.edu.cn.
  • 8 Lab for Future Health, Frontier Center of TCM Chemobiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. yaoli@shsmu.edu.cn.
  • 9 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. angela_wanghao@sjtu.edu.cn.
  • # Contributed equally.
PMID: 40702549 DOI: 10.1186/s13024-025-00875-4
Abstract

Background: Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented Amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored.

Methods: We employed a multi-omics approach integrating bulk RNA Sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice.

Results: The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/SMAD3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice.

Conclusions: This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.

Keywords

Alzheimer's disease; Astrocyte; Brain microvascular endothelial cells; Cerebrovascular endothelial extracellular vesicles; Endoglin; Neurovascular unit.

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